PROJECT SUMMARY Principal Investigator: Kathryn Jane Grande-Allen, Ph.D. Heart valve disease mandates hospitalization for almost 100,000 Americans every year. Although some of the initial causes of valve disease are well recognized, the intermediate cell-mediated disease mechanisms are largely unknown. The only effective treatment for most valve diseases is surgical repair or replacement;there are no medical or therapeutic treatments for the prevention or amelioration of valve disease. The drive to dissect potential disease mechanisms and develop new medical therapies has invigorated research in valve biology. This field is in its infancy, but has nonetheless has witnessed many recent findings about contractile, synthetic, cell communication, adhesion, and signaling characteristics of valvular interstitial cells (VICs), especially as they relate to the tissue engineering of valves and the development of calcific aortic valve disease. Nonetheless, there has been scant investigation into the metabolism of valve cells. Although recent publications have addressed how oxygen diffusion and perfusion affects valve cells and tissue engineered valves, the topic of valvular cell metabolism remains largely unaddressed. Cells within normal adult valves maintain quiescence (even within such a mechanically active tissue), but show the capacity to become activated and alter their phenotype/behavior in response to various injury or disease conditions. This activation process is quite poorly characterized, leading to several questions about the fundamental metabolic rates of VICs under these quiescent and activated conditions. It is also unknown how this metabolic rate is influenced by the environment of the cell, meaning its pericellular matrix and level of mechanical or chemical stimulation. These issues are very important given the use of exogenous stimuli in the development of tissue engineered valves, and the roles of these factors in valve remodeling and disease progression. Indeed, metabolism is recognized as the first responder to environmental stresses for most cell types. To address these questions, this research proposes to determine the fundamental metabolic rates of VICs (Aim 1). The following 2 aims will examine the effect of cytokine and hypoxic stimulation (Aim 2) and mechanical stretch (Aim 3) on metabolic rates and metabolic gene expression by VICs. This research is significant because it will provide new and fundamental information about the metabolic rates of VICs under basal and stressed culture conditions, and will establish an important new direction in the field of valve cell biology. The resulting data will complement the work of other investigators examining oxygen consumption of VICs and valve leaflets, and will guide scientists and engineers developing tissue engineered valves. This work will also promote new avenues for valve disease research, since the valve cell responses (enabled by metabolism) likely contribute to disease progression, whether the initial cause was cardiac dilatation, infection, or a congenital malformation. Information about fatty acid metabolism would be relevant to the early stages of calcific aortic valve disease, since there is a growing incidence of this condition in the setting of obesity, diabetes, and metabolic syndrome. PUBLIC HEALTH RELEVANCE: Public Health Relevance Principal Investigator: Kathryn Jane Grande-Allen, Ph.D. Heart valve disease leads to hospitalization for almost 100,000 Americans every year, but the causes of heart valve disease are a mystery, especially because much of the behavior of heart valve cells has never been previously studied. This research will study the metabolism of heart valve cells, meaning how they use sugars, fatty acids, and lactate to create fuel for their activities such as migrating and making new proteins. This research will also examine how several conditions that are used to create tissue engineered heart valves affect this metabolism. This research is also relevant due to the growing incidence of aortic valve disease in the setting of obesity, diabetes, and metabolic syndrome.